Following the observation that butyric acid induces cell differentiation in vitro [A. Leder and P. Leder, "Butyric Acid, a Potent Inducer of Erythroid Differentiation in Cultured Erythroleukemic Cells", Cell, 5, pp. 319-22 (1975)], that compound was found to demonstrate promising effects in leukemia patients, by inducing cell differentiation [A. Novogrodsky et al., "Effect of Polar Organic Compounds on Leukemic Cells", Cancer, 51, pp. 9-14 (1983)]. Aside from their use in treating .beta.-hemoglobinopathies, butyrate derivatives such as arginine butyrate, an arginine salt of butyric acid, have been shown to exert anti-tumor and anti-leukemia effects in mice [C. Chany and I. Cerutti, "Antitumor Effect Of Arginine Butyrate in Conjunction with Corynebacterium parvum and Interferon", Int. J. Cancer, 30, pp. 489-93 (1982); M. Otaka et al., "Antibody-Mediated Targeting of Differentiation Inducers To Tumor Cells: Inhibition of Colonic Cancer Cell Growth in vitro and in vivo", Biochem. Biophys. Res. Commun., 158, pp. 202-08 (1989); O. Vincent-Fiquet, J. C. Rogez, F. Boitte, M. Brazier and G. Desmet, "Effects of Arginine Butyrate and Tributyrylxylitol on Cultured Human Sarcoma Cells", Anticancer Research, 14, pp. 1823-28 (1994)].
Sodium butyrate has been found to induce apoptosis in retinoblastoma cell lines [Robert M. Conway, Michele C. Madigan, Philip L. Penfold and Francis A. Billson, "Induction of Apoptosis by Sodium Butyrate in the Human Y-79 Retinoblastoma Cell Line", Oncology Research, Vol. 7, No. 6, pp. 289-97 (1995)] and modify antigen expression in pancreatic cancer cells [Stefano Corra, Katherine Kazakoff, Masatoshi Mogaki, Martin Cano, and Parviz M. Pour, "Modification of Antigen Expression in Human and Hamster Pancreatic Cancer Cell Lines Induced by Sodium Butyrate", Teratogenesis, Carcinogenesis, and Mutagenesis, 13, pp. 199-215 (1993)].
The differentiating ability of butyrates is enhanced when administered in conjunction with other active agents. The combination of butyrates with the active metabolite of vitamin D shows enhanced differentiation of human colonic carcinoma cells in vitro [Y. Tanaka, K. K. Bush, T. M. Klauck, P. Higgins, "Enhancement of Butyrate Induced Differentiation of HT-29 Human Colon Carcinoma Cells by 1,25-Dihydroxyvitamin D.sub.3 ", Biochem. Pharmacol. 38, pp. 3859 (1989)]. Other agents known to exhibit this synergism with butyrates include all trans-retinoic acid [Z. Chen and T. Breitman, "Tributyrin: A Prodrug of Butyric Acid for Potential Clinical Application in Differentiation Therapy", Cancer Res., 54, pp. 3494-99 (1994)], TNF-.alpha. (Tumor Necrosis Factor) [Yifan Zhai et al, Development and Characterization of Recombinant Adenoviruses Encoding MART1 or gp100 for Cancer Therapy, The Journal of Immunolgy, pp. 700-710 (1996)] and dibutyryl adenosine-3',5'-cyclic monophosphate [Paul S. Ebert and Michael Salcman, "Differentiation Therapy Is Potentiated by Chemotherapy and Hyperthermia in Human and Canine Brain Tumor Cells In Vitro", Neurosurgery, Vol. 34, No. 4, pp. 657-663 (1994)].
Butyrates have also been tested for use in combination therapy in conjunction with a known therapeutic agent. A combination of Inteleukin 2 and sodium butyrate has been investigated for treatment of colo-rectal cancer [Pacale Perrin et al, An Interleukin 2/Sodium Butyrate Combination as Immunotherapy for Rat Colon Cancer Peritoneal Carcinomatosis, Gastroenterology, 107, pp. 1697-1708 (1994)].
Butyrate salts induce differentiation of colon cancer cell lines and arrest the growth of neoplastic colonocytes [O. C. Velazquez, H. M. Lederer, and J. L. Rombeau, "Butyrate and the Colonocyte. Implications for Neoplasia", Dig. Dis. Sci., 41, pp. 727-39 (1996)]. Sodium butyrate has been shown to induce apoptosis in colorectal carcinoma cell lines and to inhibit urokinase plasminogen activator and its receptor mRNA expression in colon cancer cell lines [A. Hague, D. J. Elder, D. J. Hicks, and C. Paraskeva, "Apoptosis in Colorectal Tumour Cells: Induction by the Short Chain Fatty Acids Butyrate, Propionate And Acetate and by the Bile Salt Deoxycholate", Int. J. Cancer, 60, pp. 400-6 (1995); Jinjin Dang, Yao Wang and William F. Doe, "Sodium Butyrate Inhibits Expression Of Urokinase And Its Receptor mRNAs At Both Transcription And Post-transcription Levels In Colon Cancer Cells", FEBS Letts., 359, pp. 147-50 (1995)]. Butyrates, in conjunction with a known therapeutic agent, are known to be effective in the apoptosis of colon cancer cells [John A. McBain et al, "Phorbol Ester Augments Butyrate-Induced Apoptosis Of Colon Cancer Cells", Int. J. Cancer, 67, pp. 715-723 (1996)].
In addition to colon cancer, butyrates have been investigated for the treatment of inflammatory bowel diseases, such as colitis and Crohn's disease. Butyrates enhance the synthesis of colonic mucin, a glycoprotein present in the colonic mucus. The mucus adheres to the colonic epithelium, thereby preventing invasion by colonic bacteria and protecting against damage by bacterial toxins and enzymes. Butyrate enemas are used in the treatment of diversion colitis and ulcerative colitis [W. Frankel et al, "Butyrate Increases Colonocyte Protein Synthesis In Ulcerative Colitis", Journal of Surgical Research, 57, pp. 210-214 (1994); A. Finnie et al, "Colonic Mucin Synthesis is Increased by Sodium Butyrate", Gut, 36, pp. 93-99 (1995)].
More recently, it has been suggested that butyrate may be beneficial in the treatment of cystic fibrosis (CF) by properly directing the mutant, but functional gene product of the CFTR gene to the plasma membrane [S. H. Cheng et al., Am. J. Physiol., 268, pp. L615-L624 (1995)]. Most forms of CF are linked to a mutation in the CFTR gene which causes the expressed protein to be mislocalized to the endoplasmic reticulum, rather than the plasma membrane. The CFTR gene product is a chloride ion channel. The mutant gene product retains partial ability to function as a chloride channel, but its mislocalization renders that function useless [C. Li et al., Nat. Genet., 3, pp. 311-316 (1993); G. M. Denning et al., Nature, 358, pp. 761-764 (1992)].
In connection with gene therapy, it has been shown that retroviral expression of the wild-type CFTR gene is enhanced in the presence of butyrate [J. C. Olsen et al., Hum. Gene Ther., 6, pp. 1195-1202 (1995)].
The drawbacks of all of these methods is that the forms of butyrate utilized are characterized by poor pharmacokinetics. For example, butyrate salts have the advantage of low toxicity as compared with conventional chemotherapeutic agents, but their short half-lives in vivo have been viewed as a potential obstacle in clinical settings [A. Miller et al., "Clinical Pharmacology of Sodium Butyrate in Patients with Acute Leukemia", Eur. J. Clin. Oncol., 23, pp. 1283-87 (1987); Novogrodsky et al., supra]. The rapid clearance of these agents results in an inability to deliver and maintain high plasma levels of butyrate which necessitates administration by intravenous infusion. Another potential obstacle to the use of butyrate salts is salt overload and its physiological sequelae.
In view of these observations, various prodrugs of butyric acid have been proposed for use in .beta.-hemoglobinopathy and leukemia differentiation therapies. Such prodrugs include tributyrin and n-butyric acid mono- and polyesters derived from monosaccharides [Z. Chen and T. Breitman, "Tributyrin: A Prodrug of Butyric Acid for Potential Clinical Application in Differentiation Therapy", Cancer Res., 54, pp. 3494-99 (1994); H. Newmark et al., "Butyrate as a Differentiating Agent: Pharmacokinetics, Analogues and Current Status", Cancer Letts., 78, pp. 1-5 (1994); P. Pouillart et al., "Pharmacokinetic Studies of N-Butyric Acid Mono- and Polyesters Derived From Monosaccharides", J. Pharm. Sci., 81, pp. 241-44 (1992); C. Calabresse et al, "Selective Induction Of Apoptosis In Myeloid Leukemic Cell Lines By Monoacetone Glucose-3 Butyrate", Biochem. Biophys. Res. Comm., Vol. 201, No. 1, pp. 266-82 (1994)].
Such butyrate prodrugs have not proved useful as therapeutics, however, due to factors such as short half-life, low bioavailability, low C.sub.max, or lack of effective oral deliverability. Other prodrugs, such as AN-9 and AN-10 [A. Nudelman et al., "Novel Anticancer Prodrug of Butyric Acid", J. Med. Chem., 35, pp. 687-94 (1992)], elicit metabolites that may produce formaldehyde in vivo, leading to toxic effects in patients.
Accordingly, the need exists for forms of butyrate having desirable pharmacokinetic properties for use in providing effective therapy for the target diseases discussed above.